Hypophysectomy and saralasin on mesenteric vasoconstrictor response to vasopressin CATHERINE C. Y. PANG, WILLIAM Department of Pharmacology, University Saskatchewan S?N OWO Canada
C. WILCOX, AND J. ROBERT of Saskatchewan, Saskatoon,
C. Y., WILLIAM C. WILCOX, AND J. Hypophysectomy and saralasin on mesenteric vasoconstrictor responseto vasopressin. Am. J. Physiol. 236(2): H200-H205, 1979 or Am. J. Physiol.: Heart Circ. Physiol. 5(2): H200-H205, 1979.-The dose-responserelationship of the mesenteric resistance vesselsto vasopressinwas studied in anesthetized laparotomized cats before and after hypophysectomy and again during the plateau phase of the responseto a prolonged infusion of [Sar*-Ala81angiotensin II (saralasin), a competitive antagonist of angiotensin II. Hypophysectomy and saralasin each causedan increasein superior mesenteric arterial conductance. Before hypophysectomy infusion of 0.5 mU/(min kg) of vasopressincausedmesenteric conductanceto decreasefrom 0.168to 0.156ml/(min kg mmHg), a change of only 0.012units. After hypophysectomy, the same dose reduced conductance from 0.227 to 0.179 mU/ (min kg mmHg), a changeof 0.048units. During the plateau phase of the responseto saralasin, 0.5 mU/(min kg) of vasopressin reduced conductance from 0.281 to 0.201 ml/ (min kg mmHg), a change of 0.079 units. Hypophysectomy and saralasin had little effect on the mesenteric vasoconstrictor responseto high dosesof vasopressin(2.0-10 mU/(min kg). The ineffectiveness of low dosesof vasopressinon the mesenteric resistance vesselsof the intact anesthetized, surgicallystressedanimal may be due in part to the already constricted state of the bed causedby endogenousvasopressinand angiotensin and in part due to an opposingvasodilator influence, the reflex withdrawal of the vasoconstrictor effect of endogenous vasopressin. PANG,
CATHERINE
ROBERT MCNEILL.
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OB ISERVATIONS h .ave indicated that the pressor activity of vasopressin appears to be considerably greater than was reported earlier, and that it may be sufficient to implicate the hormone in the control of arterial pressure under certain physiological or pathophysiological conditions. Infusions of vasopressin in amounts producing blood levels similar to those found following a moderate nonhypotensive hemorrhage caused an increase in arterial pressure in the conscious dog (29), confirming an earlier report in the anesthetized dog (22). It has also been reported that normally subpressor doses of vasopressin cause an elevation in arterial pressure following hypophysectomy, suggesting already high circulating levels of vasopressin may reduce the sensitivity to vasopressin in intact anesthetized animals (18). As well, the pressor activity of vasopressin has been shown to be greatly enhanced
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after baroreceptor denervation (5 >22)) ganglionic blockade with tetraethylammonium chloride (32), and in patients with idiopathic postural hypotension (32). The vasoconstrictor activity of vasopressin on the mesenteric resistance vessels may also be greater than that reported earlier in the cat (4) and in the dog (23). In these studies the dose-response relationship of the mesenteric bed to vasopressin was performed in anesthetized surgically stressed animals, conditions in which the circulating levels of vasopressin and angiotensin are elevated (2, 7, 11, 21, 23). The vasoconstrictor action of these peptides appears to explain a large portion of the high arterial pressure and low mesenteric conductance observed in anesthetized animals subjected to major surgery (unpublished observation). It seemed likely therefore, that the mesenteric bed, already partially constricted by vasopressin and angiotensin, may be less sensitive to the vasoconstrictor activity of exogenous vasopressin. Furthermore, infusion of vasopressin should cause reflex inhibition of the augmented vasopressin secretion and renin release, and the withdrawal of these vasoconstrictor influences might oppose and thus mask the vasoconstrictor effect of the exogenous vasopressin. These possibilities were tes,ted by studying the dose-response relationship of the mesenteric resistance vessels to vasopressin in anesthetized, laparotomized cats before and after hypophysectomy, and again during a prolonged infusion of [Sari-Ala81 angiotensin II (saralasin), a competitive antagonist of angiotensin II (20). METHODS
Nine cats of either sex weighing 2-4 kg were anesthetized by intraperitoneal injection of 30 mg/kg of sodium pentobarbital (Nembutal, Abbott). When reflex eye, ear or limb movements returned, additional doses (5-10 mg) of sodium pentobarbital were infused slowly through a forelimb cutaneous vein. After tracheotomy, the pituitary gland was exposed by a transpalatal approach as described in detail elsewhere (15). The abdomen was opened and a l-2 cm length of the superior mesenteric artery was dissected free from surrounding nerves and tissues. In other experiments, it was shown that this procedure did not damage the intestinal nerves since the superior mesenteric venous outflow response to stimulation of the peripheral ends of the cut greater splanchnic nerves was similar before and after dissec-
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tion (13). A noncannulating electromagnetic flow probe (Statham) and, downstream from this, a micrometercontrolled screw clamp were placed around the superior mesenteric artery. Anastomoses between the superior mesenteric artery and the inferior mesenteric and hepatic arterial vessels were tied. Arterial pressure was recorded from cannulas in the femoral artery and in a branch of the superior mesenteric artery downstream from the flow probe and clamp. A&nine vasopressin (Sigma) was infused through a forelimb cutaneous vein at rates to provide 0.5, 1 .O, 2.0, 5.0, and 10.0 mU/(min kg) of drug in each cat. Each dose was infused for 10 min to ensure that flow and pressure were steady at their new level, at which time the next higher dose was infused. From the recordings, cumulative dose-response curves were constructed. In two preliminary experiments, the cumulative dose-response curves were almost identical to the curves obtained when the various doses were infused randomly in a noncumulative fashion, i.e. )’when a recovery period was allowed between each dose. To shorten the experimental period, only cumulative dose-response curves were included in subsequent experiments. In two other cats, repeated cumulative dose-response curves were obtained to determine whether the sensitivity of the mesenteric resistance vessels to vasopressin changed with time or with previous exposure to vasopressin. In each of the five remaining cats, the dose-response relationship was studied before and after hypophysectomy and again during the plateau phase of the response to a prolonged intravenous infusion (10 pg/min) of [Sari-Ala81 angiotensin II, a competitive antagonist of angiotensin II (20). Exposure of the pituitary gland causes little or no sustained change in superior mesenteric arterial flow or arterial pressure, and significant changes in these parameters occur only when the gland is quickly removed by suction (14). In other experiments (16), 10 pg/min of [Sari-Ala81 angiotensin II completely blocked the mesenteric vasoconstrictor response to 1.0 pg/min of angiotensin II (Hypertensin, Ciba). This dose of the antagonist had no effect on the intestinal vasoconstrictor response to 1-5 mU/(min kg) of vasopressin (Pitressin, Parke-Davis) or on the response to stimulation of the intestinal nerves (10 V, 2 ms, 4/s). Recovery from the effects of each series of doses was followed for 60 min and the effects of hypophysectomy were monitored for 30 min. Arterial pressure increased significantly at the higher doses of vasopressin. To reduce the influence of autoregulation (8) on the response of the mesenteric resistance vessels to vasopressin, superior mesenteric arterial pressure was maintained at or near preinfusion control values by adjustment of the micrometer-controlled screw clamp. For comparison to the results obtained in the cat by Cohen et al. (4), the responses to vasopressin were calculated in conductance units (ml/ (min. kg. mmHg) and the conductance values recorded during the plateau phase of a response to the drug were expressed as a percentage of the control conductance values recorded shortly before the infusion began. Because additional information is gained by examining the absolute con-
H201 ductance values, these values were plotted as well. Statistical analysis was carried out by analysis of variance for repeated measures using logarithm-transformed data. In all cases the variance was assessed as being homogenous on the logarithm-transformed data by Tukey’s test for nonadditivity. Multiple comparisons of different treatments were accomplished by Duncan’s multiple range test. RESULTS
The control values for femoral arterial pressures and for superior mesenteric arterial flows and conductances recorded immediately before infusions of vasopressin and before hypophysectomy and infusion of [Sari-Ala81 angiotensin II are shown in Table 1 and are within the range of those reported to occur in the anesthetized, surgically stressed cat (12-16). Vasopressin in intact animals. Infusions of vasopressin from 0.5 to 10 mU/(min kg) caused a dose-related decrease in superior mesenteric arterial conductance in animals with an intact pituitary gland and with a functioning renin-angiotensin system (Fig. 1). However, the absolute conductance values (ml/ (min kg* mmHg)) recorded during the response to the lowest dose of vasopressin (0.5 mU/(min kg)) were not significantly different (P > 0.05) from the control conductance values (Fig. 2) and conductance values significantly different from control (P c 0.05) occurred only when the dose of vasopressin was 1.0 mU/(min kg) or larger. Except for the largest dose (10 mU/(min kg)) of vasopressin, the responses recorded (Fig. 1) closely matched those reported by Cohen et al. (4), and together with their data indicate that the mesenteric resistance vessels appear relatively unresponsive to 0.5 mU1 (min kg) of vasopressin. The various doses of vasopressin caused only small changes in femoral arterial pressure (Fig. 1). The pressure values (mmHg) recorded during 0.5, 1.0, and 2.0 mU/(min . kg) of vasopressin were not significantly different (P > 0.10) from control values (Fig. 2), and pressure values significantly different from control (P c 0.05) occurred only when the dose of vasopressin was 5.0 or 10.0 mU/(min. kg). l
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TABLE 1. Control values recorded immediately prior to infusions of vasopressin and before hypophysectomy and infusion of [Sari-Ala81 angiotensin II FAP
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Vasopressin, intact 128 2 2 21.34 + 0.74 0.168 t 0.007 animal Hypophysectomy 124 2 2 22.43 + 0.78 0.184 t 0.007 Vasopressin after 122 +, 2 27.29 2 0.95 0.227 t 0.008 hypophysectomy [Sari-Alas] angiotensin 123 +, 2 23.68 2 0.81 0.198 t 0.007 II Vasopressin, during 110 k 2 30.34 + 1.04 0.281 t 0.011 [ Sari-Ala81 angiotensin II Values are means * SE for five cats. Femoral arterial pressures, FAP, mmHg, superior mesenteric arterial flows, SMAF, ml/ (min kg), and superior mesenteric arterial conductances, SMAC, ml/ (min kg mmHa). l
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pressin dose-response relationship occurred in the lower dosage range (Fig. 2). Thus, in intact animals, 0.5 mU/ (min. kg) of vasopressin had caused mesenteric conductance to decrease from 0.168 to 0.156 ml/(min kg mmHg), a change of only 0.012 units. However, the same dose administered after hypophysectomy caused conductance to decrease from 0.227 to 0.179 ml/(minkg*mmHg), a change of 0.048 units. Thus 0.5 mU/(min kg) caused a 4.0-fold greater decrease in conductance when the pituitary gland had been removed. In the higher dosage range the conductance values recorded in response to a particular dose of the drug after hypophysectomy were almost identical to the corresponding values recorded before hypophysectomy (Fig. 2). Thus, increasing the dose of vasopressin, for example from 2.0 to 5.0 mU/ . (min. kg), caused almost the same decrement in conductance in the presence or absence of the pituitary gland. Thus, at high doses of vasopressin, the pituitary gland appears to exert little influence on the apparent responsiveness of the mesenteric resistance vessels to was vasopressin, and the influence of the pituitary evident only in the lower dosage range. The values for femoral arterial pressure recorded during 2.0, 5.0, and 10.0 mU/(minkg) of vasopressin were significantly different (P c 0.05) from the preinfusion control value (Fig. 2). These doses of vasopressin caused a small, but significantly larger (P .< 0.05), increase in arterial pressure (percent control, Fig. 1) than had occurred when the pituitary gland had been intact (Fig. 1). l
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1. Effect of vasopressin on femoral arterial pressure and superior mesenteric arterial conductance (or0control [Table I]) in five cats when the pituitary was intact, following hypophysectomy, and in hypophysectomized animals during a prolonged infusion of [SariAla81 angiotensin II. Values represent means +, SE. FIG.
Vusopressin after hypophysectomy . Hypophysectomy caused an increase in mesenteric conductance that reached a new plateau 15-30 min after removal of the gland (Fig. 3). The values recorded 30 min aftir hypophysectomy were significantly different from the control values recorded immediately before the gland was removed (P c 0.01). Arterial pressure was 124 t 2 mmHg before, and 122 t 2 mmHg after hypophysectomy. The results suggest that the pituitary gland exerts a significant vasoconstrictor influence on the mesenteric resistance vessels in the anesthetized, laparotomized cat. In the absence of the pituitary gland, each dose of vasopressin caused a significantly larger (P c 0.05) decrease in mesenteric conductance as a percentage of control than had occurred when the gland had been intact (Fig. 1). Thus the dose-response curve was shifted in a manner suggesting increased responsiveness of the mesenteric resistance vessels to vasopressin. Comparison of absolute conductance values indicated that the most dramatic effect of hypophysectomy on the vaso-
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2. Effect of vasopressin on femoral arterial pressure and superior mesenteric arterial conductance in five cats when pituitary was intact (hatched columns), following hypophysectomy (open columns), and in hypophysectomized animals during a prolonged infusion of [Sax+-Alaa] angiotensin II (shaded columns). Columns shown above zero mU/(min kg) of vasopressin represent control conductance values recorded immediately prior to infusions of vasopressin. Values represent means 2 SE. FIG.
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FIG. 3. Effect of hypophysectomy and intravenous infusion of [Sari-Ala81 angiotensin II on superior mesenteric arterial conductance in five anesthetized laparotomized cats.
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Vasopressin after hypophysectomy and during @a+Ala81 angiotensin II. Infusion of [Sari-Ala”] angiotensin
II (10 pg/min iv) after hypophysectomy caused an increase in superior mesenteric arterial conductance that reached a new plateau about 10 min after beginning the infusion (Fig. 3). The values recorded 10 min after beginning the infusion were significantly different from the control values recorded immediately before the infusion began (P < 0.01). Associated with the vasodilatation was a fall in arterial pressure from 123 t 2 to 110 t 2 mmHg (P c 0.01). Thus, in the absence of the pituitary gland, circulatory angiotensin II appears to exert a large vasoconstrictor influence on the mesenteric resistance vessels in the anesthetized, laparotomized cat. In the absence of the pituitary gland and a functioning renin-angiotensin system, each dose of vasopressin caused a significantly larger (P < 0.05) decrease in mesenteric conductance as a percentage of control than had occurred in intact animals (Fig. 1). Again, comparison of absolute conductance values indicates that the most dramatic effect of the angiotensin II antagonist in hypophysectomized animals occurred in the lower dosage range (Fig. 2). Thus 0.5 mU/(min. kg) of vasopressin caused mesenteric conductance to decrease from 0.281 to 0.201 ml/(mine kg*mmHg), a 6.7-fold greater decrease than had occurred in intact animals (P c 0.01) and a 1.7-fold greater decrease than had occurred after hypophysectomy (P < 0.01). As the dosage of vasopressin increased, the conductance values recorded in response to a particular dose of the drug approached the corresponding values recorded earlier; thus the decrement in conductance was similar to what had occurred during the first two infusions. Therefore, in the higher dosage range, the pituitary gland and renin-angiotensin system appear to exert little influence on the responsiveness of the mesenteric resistance vessels to vasopressin, and the influence of these factors was evident only in the lower dosage range. The values for femoral arterial pressure recorded during 2.0, 5.0, and 10.0 mU/(min.kg) of vasopressin
were significantly different (P c 0.0025) from the preinfusion control value (Fig. 2). These doses of vasopressin caused a small, but significantly larger (P < 0.05), increase in arterial pressure (percent control, Fig. 1) than had occurred in intact animals, although the increase was not significantly different (P > 0.5) from that which occurred after hypophysectomy alone (Fig. 1) ‘Repeated dose-response curves in intact
animals.
Three dose-response curves to vasopressin were obtained in each of two cats. The second and third doseresponse curves in each cat were very similar to the first curve obtained in the same cat. It appeared that the sensitivity of the mesenteric resistance vessels to vasopressin does not change significantly with time or with previous exposure to vasopressin, and that the changes in sensitivity observed in other experiments were due to the interventions of hypophysectomy and the angiotensin II antagonist. DISCUSSION
The observation that hypophysectomy and [SariAla81 angiotensin II caused an increase in mesenteric conductance suggests that circulating vasopressin and angiotensin exert a major vasoconstrictir influence on the mesenteric resistance vessels in the anesthetized surgically stressed cat. It has not been proven that the effects of hypophysectomy were due solely to removal of the vasopressin system. However, following removal of the gland, conductance increased slowly and, in all animals, reached a new plateau 15-30 min later. The time course of this vasodilatation was similar to that of stopping a vasopressin infusion and parallels the predicted rate of elimination for vasopressin. Assuming the half-life of vasopressin in the anesthetized animal is approximately 5-6 min (10) and that it requires 4 to 5 half-lives for a compound eliminated by first-order kinetics to reach new steady-state levels, it follows that circulating levels of vasopressin should approach negligible values 20-30 min after removal of the major source
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of the hormone. On the basis of these observations and assumptions, we interpret the changes in conductance that follow hypophysectomy as primarily due to elimination of circulating vasopressin. The effects of [SariAlas] angiotensin II are more easily interpreted. The compound is a weak partial agonist (17). It competitively antagonizes angiotensin II and has little other known biological activity (20). The vasodilatation caused by hypophysectomy and [Sari-Ala81 angiotensin II are in agreement with other data from our laboratory (14) and we conclude that the high arterial pressure and low mesenteric conductance observed in acute experiments is in part due to the vasoconstrictor action of circulating vasopressin and angiotensin. We also conclude that the effect of these endogenous peptides on the mesenteric resistance vessels reduces the apparent sensitivity of these vessels to exogenous vasopressin. Except for the largest dose of 10 mU/ (min kg) of vasopressin, the responses recorded in our intact animals (Fig. 1) closely .matched those reported by Cohen et al. Our combined results indicate that the mesenteric resistance vessels in the cat appear relatively unresponsive to 0.5 mU/(min kg) of vasopressin. In the dog, 2 and 4 mU/(min kg) of vasopressin caused no significant change in mesenteric conductance and 8 mU/(min kg) was required to induce a significant change in this parameter (23). However, this apparent lack of sensitivity appears to be in part due to the influence of the vasopressin system and renin-angiotensin system since 0.5 mU/(min kg) of vasopressin, a dose which caused only a small change in conductance in intact animals, caused a 6.7-fold greater change in conductance when the influence of these systems were absent (Fig. 2). The lack of effect of 0.5 mU/(min . kg) of vasopressin in intact animals may be due to several factors. It can be argued that the ineffectiveness of this dose of vasopressin is because the mesenteric bed is already constricted and that we are approaching the plateau level of the dose-response curve. This may well be part of the explanation. However, since baroreceptor activity influences vasopressin secretion (26) and since vasopressin appears to account in part for the constricted state of the mesenteric bed in our intact animals, it seems reasonable to assume that administration of a vasoconstrictor agent would cause reflex inhibition of vasopressin secretion and that concurrent inactivation of circulating vasopressin should then’ constitute a vasodilator influence which opposes the vasoconstrictor activity of exogenous vasopressin. Consistent with this assumption is the observation that infusion of the pressor agent, norepinephrine, suppresses the release of vasopressin (1, 27) via the baroreceptor reflex (1). It seems likely that infusion of a&other vasoconstrictor agent, vasopressin, also should cause reflex inhibition of vasopressin secretion. Thus the small effect of 0.5 mU/ (min. kg) of vasopressin in animals with a functioning vasopressin system may be due in part .to two opposing influences: the vasoconstrictor action of exogenous vasopressin and the withdrawal of the vasoconstrictor influence of endogenous vasopressin. Because intravenous infusions of vasopressin inhibit renin release (3, l
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24, 30, 31), it is tempting to suggest that withdrawal of the vasoconstrictor influence of the renin-angiotensin system may also have contributed to the lack of potency of vasopressin in intact animals. However, the half-life of renin is long (6) and although the secretion rate of renin may be reduced in our experiments during in% sion of vasopressin, plasma renin activity and the circulating levels of angiotensin may fall only slowly. In view of these considerations, we suggest that the ineffectiveness of low doses of vasopressin on the mesenteric resistance vessels in the anesthetized, surgically stressed animal is due in part to the already constricted state of the bed caused by endogenous vasopressin and angiotensin, and in part due to an opposing vasodilator influence, namely the reflex inhibition of vasopressin secretion and concurrent elimination of endogenous vasopressin. Despite marked vasoconstriction of the mesenteric resistance vessels by vasopressin, the increases in femoral arterial pressure were small. Since other vascular beds respond to vasopressin, and total peripheral resistance is elevated (23), it is likely that cardiac output was reduced during our infusions, a probability consistent with the role of total peripheral resistance in the control of venous return (9), and an observation reported to occur in the dog ,during infusions of vasopressin (23). The small changes in arterial pressure are consistent also with an active baroreceptor reflex. Cowley, Monos, and Guyton showed that doses of vasopressin which caused marked pressor responses in baroreceptor-denervated conscious dogs caused little change in blood pressure when the buffer action of the baroreceptor reflex was intact and allowed to compensate (5), a finding which confirmed an earlier report in the anesthetized dog (22). In our experiments, reflex withdrawal of sympathetic nervous system activity also may have attenuated the pressor response to exogenous vasopressin at least partly by reducing the tone in capacitance vessels, thereby contributing to the fall in venous return and cardiac output. The change in mesenteric conductance caused by doses as low as 0.5 mU/(min . kg) of vasopressin suggests a role for this hormone in the control of mesenteric conductance under certain pathophysiological conditions. Although data on the plasma clearance of vasopressin in the cat is inadequate, the mean plasma clearance values for vasopressin in the pentobarbitalanesthetized dog ranged from 10.0 to 14.9 ml/(min kg) in six different studies (10). Since the half-life of the hormone in the cat is similar to that in the dog (10) and assuming the volume of distribution is similar in the two species, then the plasma clearance of vasopressin in the cat may also be similar to that found in the dog. Thus an infusion of 0.5 mU/(min 9kg) of the drug should cause an elevation in the steady-state plasma concentration of vasopressin in the range of 34 to 50 @/ml in our hypophysectomized animals, a level within the range reported to occur following major surgery (2, 19) or mild blood loss (lo-15% of blood volume) (25, 26, 28). These findings on the sensitivity of the mesenteric resistance vessels to vasopressin are consistent with other data suggesting an important role for vasopressin
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in the control of the mesenteric resistance vessels following major surgery (14), and in the mechanism of the intestinal vasoconstriction following volume depletion induced by hemorrhage (l5), or by administration of diuretics (13, 16).
We are indebted to the Saskatchewan Heart Foundation and to Our Lady of the Prairies Foundation for grants in support of this work. We thank Dr. A. W. Castellion of the Norwich Pharmacal. c o. f or a generous supply of [Sari-Ala81 angiotensin II. C. C. Y. Pang is a fellow of the Canadian Heart Foundation. Received 20 June 1977; accepted in final form 28 August 1978.
REFERENCES 1. BERL, T., P. CADNAPAPHORNCHAI, J. A. HARBOTTLE, AND R. W. SCHRIER. Mechanism of suppression of vasopressin during alphaadrenergic stimulation with norepinephrine. J. CZin. Invest. 53: 219-227,1974. 2. BONJOUR, J. P., AND R. L. MALVIN. Plasma concentrations of ADH in conscious and anesthetized dogs. Am. J. Physiol. 218: 1128-1132,197O. 3. BUNAG, R. D., I. H. PAGE, AND J. W. MCCUBBIN. Inhibition of renin release by vasopressin and angiotensin. Cardiovas. Res. 1: 67-73,1967. 4. COHEN, M. M., D. S. SITAR, J. R. MCNEILL, AND C. V. GREENWAY. Vasopressin and angiotensin on resistance vessels of spleen, intestine, and liver. Am. J. Physiol. 218: 1704-1706, 1970. 5. COWLEY, JR., A. W., E. MONOS, AND A. C. GUYTON. Interaction of vasopressin and the baroreceptor reflex system in the regulation of arterial blood pressure in the dog. Circ. Res. 34: 505-514, 1974. 6. LARAGH, J. H., AND J. E. SEALEY. The renin-angiotensin-aldosterone hormonal system and regulation of sodium, potassium, and blood pressure homeostasis. In: Handbook of Physiology. RenaZ Physiology, edited by J. Orloff and R. W. Berliner. Washington, D.C.: Am. Physiol. Sot., 1973, sect. 8, p. 831-908. 7. JOHNSON, M. D., AND R. L. MALVIN. Plasma renin activity during pentobarbital anesthesia and graded hemorrhage in dogs. Am. J. Physiol. 229: 1098-1101,1975. 8. JOHNSON, P. C. Autoregulation of intestinal blood flow. Am. J. PhysioZ. 199: 311-318, 1960. 9. JONES, C. E.; E. E. SMITH, AND J. W. CROWELL. Cardiac output and physiological mechanisms in circulatory shock. In: i&?P InternationaL Review of Science. Cardiovascular PhysioZogy, edited by A. C. Guyton and C. E. Jones. Baltimore: University Park Press, 1974, ser. 1, vol. 1, p. 233-258. 10. LAUSON, H. D. Metabolism of the neurohypophysial hormones. In: Handbook of PhysioZogy: Endocrinology, edited by R. 0. Greep and E. B. Astwood. Washington, D.C.: Am. Physiol. Sot. 1974, sect. 7, vol. 4, p. 287-393. 11. MCKENZIE, J. K., J. W. RYAN, AND M. R. LEE. Effect of laparotcmy on plasma renin activity in the rabbit. Nature 215: 542-543,1967. 12. MCNEILL, J. R. Escape of intestinal resistance vessels to angiotensin II. Can. J. Physiol. PhurmacoZ. 52: 458-464,1974. 13. MCNEILL, J. R. Intestinal vasoconstriction following diureticinduced volume depletion: role of angiotensin and vasopressin. Can. J. Physiol. PharmacoZ. 52: 829-839, 1974. 14. MCNEILL, J. R., W. C. WILCOX, AND C. C. Y. PANG. Vasopressin and angiotensin: reciprocal mechanisms controlling mesenteric conductance. Am. J. Physiol. 232: H260-H266, 1977 or Am. J. PhysioZ.: Heart Circ. Physiol. 1: H260-H266,1977. 15. MCNEILL, J. R., R. D. STARK, AND C. V. GREENWAY. Intestinal vasoconstriction after hemorrhage: roles of vasopressin and angiotensin. Am. J. Physiol. 219: 1342-1347, 1970. 16. MCNEILL, J. R., W. C. WILCOX, AND R. REGNAULT. Effect of SariAla8 angiotensin II and hypophysectomy on the intestinal resistance vessels and blood pressure following furosemide-induced volume depletion. Can. J. PhysioZ. Pharmacol. 54: 373-380,1976.
17. MIMRAN, A., K. J. HINRICHS, AND N. K. HOLLENBERG. Characterization of smooth muscle receptors for angiotensin: studies with an antagonist. Am. J. Physiol. 226: 185-190, 1974. 18. MONOS, E., E. KOLTAY, AND A. G. B. KOVACH. Adrenal blood flow and corticosteroid secretion: III. Effect of vasopressin on blood circulation and corticosteroid secretion in the dog before and after acute hypophysectomy. Actu Physiol. Acad. Sci. Hung. 31: 149-157,1967. 19. MORAN, H., F. W. MILTENBERGER, W. A. SHUAYB, AND B. ZIMMERMANN . The relationship of antidiuretic hormone secretion to surgical stress. Surgery 56: 99-108,1964. 20. PALS, D. T., F. D. MASUCCI, G. S. DENNING JR., F. SIPOS, AND D. C. FESSLER. Role of the pressor action of angiotensin II in experimental hypertension. Circ. Res. 29: 673-681, 1971. 21. PETTINGER, W. A., K. TANAKA, K. KEETON, W. B. CAMPBELL, AND S. N. BRINKS. Renin release, an artifact of anesthesia and its implications in rats. Proc. Sot. Exp. BioZ. Med. 148: 625-630, 1975. 22. ROCHA E SILVA M., JR., AND M. ROSENBERG. The release of vasopressin in response to hemorrhage and its role in the mechanism of blood pressure regulation. J. PhysioZ. London 202: 535-557,1969. 23. SCHMID, P. G., F. M. ABBOUD, M. G. WENDLING, E. S. RAMBERG, A. L. MARK, D. D. HEISTAD, AND J. ‘W. ECKSTEIN. Regional vascular effects of vasopressin: plasma levels and circulatory responses. Am. J. Physiol. 227: 998-1004,1974. 24. SHADE, R. E., J. 0. DAVIS, J. A. JOHNSON, R. W. GOTSHALL, AND W. S. SPIELMAN. Mechanism of action of angiotensin II and antidiuretic hormone on renin secretion. Am. J. PhysioZ. 224: 926-929,1973. 25. SHADE, R. E., AND L. SHARE. Vasopressin release during nonhypotensive hemorrhage and angiotensin II infusion. Am. J. PhysioZ. 228: 149-154,1975. 26. SHARE, L. Blood pressure, blood volume and the release of vasopressin. In: Handbook of Physiology. Endocrinology, edit.ed by R. 0. Greep and E. B. Astwood. Washington, D.C.: Am. Physiol. Sot., 1974, sect. 7, vol. 4, p. 243-256. 27. SHIMAMOTO, K., AND M. MIYAHARA. Effect of norepinephrine infusion on plasma vasopressin levels in normal human subjects. J. CZin. EndocrinoZ. Metab. 43: 201-204, 1976. 28. SZCZEPANSKA~ADOWSKA, E. The activity of the hypothalamohypophysial antidiuretic system in conscious dogs I. The influence of isosmotic blood volume changes. Pfluegers Arch. 335: 139-146, 1972. 29. SZCZEPANSKA-SADOWSKA, E. Hemodynamic effects of a moderate increase of the plasma vasopressin level in conscious dogs. Pfluegers Arch. 338: 313-322,1973. 30. TAGAWA, H., A. J. VANDER, J-P. BONJOUR, AND R. L. MALVIN. Inhibition of renin secretion by vasopressin in unanesthetized sodium-deprived dogs. Am. J. PhysioZ. 220: 949-951,197l. 31. VANDER, A. J. Inhibition of renin release in the dog by vasopressin and vasotocin. Circ. Res. 23: 605-609, 1968. 32. WAGNER, JR.,’ H. N., AND E. BRAUNWALD. The pressor effect of the antidiuretic principle of the posterior pituitary in orthostatic hypotension. J. CZin. Invest. 35: 1412-1418, 1956.
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C. WILCOX, AND J. ROBERT of Saskatchewan, Saskatoon,
C. Y., WILLIAM C. WILCOX, AND J. Hypophysectomy and saralasin on mesenteric vasoconstrictor responseto vasopressin. Am. J. Physiol. 236(2): H200-H205, 1979 or Am. J. Physiol.: Heart Circ. Physiol. 5(2): H200-H205, 1979.-The dose-responserelationship of the mesenteric resistance vesselsto vasopressinwas studied in anesthetized laparotomized cats before and after hypophysectomy and again during the plateau phase of the responseto a prolonged infusion of [Sar*-Ala81angiotensin II (saralasin), a competitive antagonist of angiotensin II. Hypophysectomy and saralasin each causedan increasein superior mesenteric arterial conductance. Before hypophysectomy infusion of 0.5 mU/(min kg) of vasopressincausedmesenteric conductanceto decreasefrom 0.168to 0.156ml/(min kg mmHg), a change of only 0.012units. After hypophysectomy, the same dose reduced conductance from 0.227 to 0.179 mU/ (min kg mmHg), a changeof 0.048units. During the plateau phase of the responseto saralasin, 0.5 mU/(min kg) of vasopressin reduced conductance from 0.281 to 0.201 ml/ (min kg mmHg), a change of 0.079 units. Hypophysectomy and saralasin had little effect on the mesenteric vasoconstrictor responseto high dosesof vasopressin(2.0-10 mU/(min kg). The ineffectiveness of low dosesof vasopressinon the mesenteric resistance vesselsof the intact anesthetized, surgicallystressedanimal may be due in part to the already constricted state of the bed causedby endogenousvasopressinand angiotensin and in part due to an opposingvasodilator influence, the reflex withdrawal of the vasoconstrictor effect of endogenous vasopressin. PANG,
CATHERINE
ROBERT MCNEILL.
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cat; anti-diuretic hormone; dose-response relationship
OB ISERVATIONS h .ave indicated that the pressor activity of vasopressin appears to be considerably greater than was reported earlier, and that it may be sufficient to implicate the hormone in the control of arterial pressure under certain physiological or pathophysiological conditions. Infusions of vasopressin in amounts producing blood levels similar to those found following a moderate nonhypotensive hemorrhage caused an increase in arterial pressure in the conscious dog (29), confirming an earlier report in the anesthetized dog (22). It has also been reported that normally subpressor doses of vasopressin cause an elevation in arterial pressure following hypophysectomy, suggesting already high circulating levels of vasopressin may reduce the sensitivity to vasopressin in intact anesthetized animals (18). As well, the pressor activity of vasopressin has been shown to be greatly enhanced
SEVERAL
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McNEILL
after baroreceptor denervation (5 >22)) ganglionic blockade with tetraethylammonium chloride (32), and in patients with idiopathic postural hypotension (32). The vasoconstrictor activity of vasopressin on the mesenteric resistance vessels may also be greater than that reported earlier in the cat (4) and in the dog (23). In these studies the dose-response relationship of the mesenteric bed to vasopressin was performed in anesthetized surgically stressed animals, conditions in which the circulating levels of vasopressin and angiotensin are elevated (2, 7, 11, 21, 23). The vasoconstrictor action of these peptides appears to explain a large portion of the high arterial pressure and low mesenteric conductance observed in anesthetized animals subjected to major surgery (unpublished observation). It seemed likely therefore, that the mesenteric bed, already partially constricted by vasopressin and angiotensin, may be less sensitive to the vasoconstrictor activity of exogenous vasopressin. Furthermore, infusion of vasopressin should cause reflex inhibition of the augmented vasopressin secretion and renin release, and the withdrawal of these vasoconstrictor influences might oppose and thus mask the vasoconstrictor effect of the exogenous vasopressin. These possibilities were tes,ted by studying the dose-response relationship of the mesenteric resistance vessels to vasopressin in anesthetized, laparotomized cats before and after hypophysectomy, and again during a prolonged infusion of [Sari-Ala81 angiotensin II (saralasin), a competitive antagonist of angiotensin II (20). METHODS
Nine cats of either sex weighing 2-4 kg were anesthetized by intraperitoneal injection of 30 mg/kg of sodium pentobarbital (Nembutal, Abbott). When reflex eye, ear or limb movements returned, additional doses (5-10 mg) of sodium pentobarbital were infused slowly through a forelimb cutaneous vein. After tracheotomy, the pituitary gland was exposed by a transpalatal approach as described in detail elsewhere (15). The abdomen was opened and a l-2 cm length of the superior mesenteric artery was dissected free from surrounding nerves and tissues. In other experiments, it was shown that this procedure did not damage the intestinal nerves since the superior mesenteric venous outflow response to stimulation of the peripheral ends of the cut greater splanchnic nerves was similar before and after dissec-
0363-6l35/79/~-~$01.25
Copyright
@ 1979 the American
Physiological
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Society
VASOPRESSIN
ON INTESTINAL
RESISTANCE
VESSELS
tion (13). A noncannulating electromagnetic flow probe (Statham) and, downstream from this, a micrometercontrolled screw clamp were placed around the superior mesenteric artery. Anastomoses between the superior mesenteric artery and the inferior mesenteric and hepatic arterial vessels were tied. Arterial pressure was recorded from cannulas in the femoral artery and in a branch of the superior mesenteric artery downstream from the flow probe and clamp. A&nine vasopressin (Sigma) was infused through a forelimb cutaneous vein at rates to provide 0.5, 1 .O, 2.0, 5.0, and 10.0 mU/(min kg) of drug in each cat. Each dose was infused for 10 min to ensure that flow and pressure were steady at their new level, at which time the next higher dose was infused. From the recordings, cumulative dose-response curves were constructed. In two preliminary experiments, the cumulative dose-response curves were almost identical to the curves obtained when the various doses were infused randomly in a noncumulative fashion, i.e. )’when a recovery period was allowed between each dose. To shorten the experimental period, only cumulative dose-response curves were included in subsequent experiments. In two other cats, repeated cumulative dose-response curves were obtained to determine whether the sensitivity of the mesenteric resistance vessels to vasopressin changed with time or with previous exposure to vasopressin. In each of the five remaining cats, the dose-response relationship was studied before and after hypophysectomy and again during the plateau phase of the response to a prolonged intravenous infusion (10 pg/min) of [Sari-Ala81 angiotensin II, a competitive antagonist of angiotensin II (20). Exposure of the pituitary gland causes little or no sustained change in superior mesenteric arterial flow or arterial pressure, and significant changes in these parameters occur only when the gland is quickly removed by suction (14). In other experiments (16), 10 pg/min of [Sari-Ala81 angiotensin II completely blocked the mesenteric vasoconstrictor response to 1.0 pg/min of angiotensin II (Hypertensin, Ciba). This dose of the antagonist had no effect on the intestinal vasoconstrictor response to 1-5 mU/(min kg) of vasopressin (Pitressin, Parke-Davis) or on the response to stimulation of the intestinal nerves (10 V, 2 ms, 4/s). Recovery from the effects of each series of doses was followed for 60 min and the effects of hypophysectomy were monitored for 30 min. Arterial pressure increased significantly at the higher doses of vasopressin. To reduce the influence of autoregulation (8) on the response of the mesenteric resistance vessels to vasopressin, superior mesenteric arterial pressure was maintained at or near preinfusion control values by adjustment of the micrometer-controlled screw clamp. For comparison to the results obtained in the cat by Cohen et al. (4), the responses to vasopressin were calculated in conductance units (ml/ (min. kg. mmHg) and the conductance values recorded during the plateau phase of a response to the drug were expressed as a percentage of the control conductance values recorded shortly before the infusion began. Because additional information is gained by examining the absolute con-
H201 ductance values, these values were plotted as well. Statistical analysis was carried out by analysis of variance for repeated measures using logarithm-transformed data. In all cases the variance was assessed as being homogenous on the logarithm-transformed data by Tukey’s test for nonadditivity. Multiple comparisons of different treatments were accomplished by Duncan’s multiple range test. RESULTS
The control values for femoral arterial pressures and for superior mesenteric arterial flows and conductances recorded immediately before infusions of vasopressin and before hypophysectomy and infusion of [Sari-Ala81 angiotensin II are shown in Table 1 and are within the range of those reported to occur in the anesthetized, surgically stressed cat (12-16). Vasopressin in intact animals. Infusions of vasopressin from 0.5 to 10 mU/(min kg) caused a dose-related decrease in superior mesenteric arterial conductance in animals with an intact pituitary gland and with a functioning renin-angiotensin system (Fig. 1). However, the absolute conductance values (ml/ (min kg* mmHg)) recorded during the response to the lowest dose of vasopressin (0.5 mU/(min kg)) were not significantly different (P > 0.05) from the control conductance values (Fig. 2) and conductance values significantly different from control (P c 0.05) occurred only when the dose of vasopressin was 1.0 mU/(min kg) or larger. Except for the largest dose (10 mU/(min kg)) of vasopressin, the responses recorded (Fig. 1) closely matched those reported by Cohen et al. (4), and together with their data indicate that the mesenteric resistance vessels appear relatively unresponsive to 0.5 mU1 (min kg) of vasopressin. The various doses of vasopressin caused only small changes in femoral arterial pressure (Fig. 1). The pressure values (mmHg) recorded during 0.5, 1.0, and 2.0 mU/(min . kg) of vasopressin were not significantly different (P > 0.10) from control values (Fig. 2), and pressure values significantly different from control (P c 0.05) occurred only when the dose of vasopressin was 5.0 or 10.0 mU/(min. kg). l
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TABLE 1. Control values recorded immediately prior to infusions of vasopressin and before hypophysectomy and infusion of [Sari-Ala81 angiotensin II FAP
SMAF
SMAC
Vasopressin, intact 128 2 2 21.34 + 0.74 0.168 t 0.007 animal Hypophysectomy 124 2 2 22.43 + 0.78 0.184 t 0.007 Vasopressin after 122 +, 2 27.29 2 0.95 0.227 t 0.008 hypophysectomy [Sari-Alas] angiotensin 123 +, 2 23.68 2 0.81 0.198 t 0.007 II Vasopressin, during 110 k 2 30.34 + 1.04 0.281 t 0.011 [ Sari-Ala81 angiotensin II Values are means * SE for five cats. Femoral arterial pressures, FAP, mmHg, superior mesenteric arterial flows, SMAF, ml/ (min kg), and superior mesenteric arterial conductances, SMAC, ml/ (min kg mmHa). l
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PANG,
WILCOX,
AND McNEILL
pressin dose-response relationship occurred in the lower dosage range (Fig. 2). Thus, in intact animals, 0.5 mU/ (min. kg) of vasopressin had caused mesenteric conductance to decrease from 0.168 to 0.156 ml/(min kg mmHg), a change of only 0.012 units. However, the same dose administered after hypophysectomy caused conductance to decrease from 0.227 to 0.179 ml/(minkg*mmHg), a change of 0.048 units. Thus 0.5 mU/(min kg) caused a 4.0-fold greater decrease in conductance when the pituitary gland had been removed. In the higher dosage range the conductance values recorded in response to a particular dose of the drug after hypophysectomy were almost identical to the corresponding values recorded before hypophysectomy (Fig. 2). Thus, increasing the dose of vasopressin, for example from 2.0 to 5.0 mU/ . (min. kg), caused almost the same decrement in conductance in the presence or absence of the pituitary gland. Thus, at high doses of vasopressin, the pituitary gland appears to exert little influence on the apparent responsiveness of the mesenteric resistance vessels to was vasopressin, and the influence of the pituitary evident only in the lower dosage range. The values for femoral arterial pressure recorded during 2.0, 5.0, and 10.0 mU/(minkg) of vasopressin were significantly different (P c 0.05) from the preinfusion control value (Fig. 2). These doses of vasopressin caused a small, but significantly larger (P .< 0.05), increase in arterial pressure (percent control, Fig. 1) than had occurred when the pituitary gland had been intact (Fig. 1). l
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after
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1. Effect of vasopressin on femoral arterial pressure and superior mesenteric arterial conductance (or0control [Table I]) in five cats when the pituitary was intact, following hypophysectomy, and in hypophysectomized animals during a prolonged infusion of [SariAla81 angiotensin II. Values represent means +, SE. FIG.
Vusopressin after hypophysectomy . Hypophysectomy caused an increase in mesenteric conductance that reached a new plateau 15-30 min after removal of the gland (Fig. 3). The values recorded 30 min aftir hypophysectomy were significantly different from the control values recorded immediately before the gland was removed (P c 0.01). Arterial pressure was 124 t 2 mmHg before, and 122 t 2 mmHg after hypophysectomy. The results suggest that the pituitary gland exerts a significant vasoconstrictor influence on the mesenteric resistance vessels in the anesthetized, laparotomized cat. In the absence of the pituitary gland, each dose of vasopressin caused a significantly larger (P c 0.05) decrease in mesenteric conductance as a percentage of control than had occurred when the gland had been intact (Fig. 1). Thus the dose-response curve was shifted in a manner suggesting increased responsiveness of the mesenteric resistance vessels to vasopressin. Comparison of absolute conductance values indicated that the most dramatic effect of hypophysectomy on the vaso-
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2. Effect of vasopressin on femoral arterial pressure and superior mesenteric arterial conductance in five cats when pituitary was intact (hatched columns), following hypophysectomy (open columns), and in hypophysectomized animals during a prolonged infusion of [Sax+-Alaa] angiotensin II (shaded columns). Columns shown above zero mU/(min kg) of vasopressin represent control conductance values recorded immediately prior to infusions of vasopressin. Values represent means 2 SE. FIG.
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VASOPRESSIN
ON INTESTINAL
RESISTANCE
H203
VESSELS
160
150
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FIG. 3. Effect of hypophysectomy and intravenous infusion of [Sari-Ala81 angiotensin II on superior mesenteric arterial conductance in five anesthetized laparotomized cats.
o-0 OP 110
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MINUTES
Vasopressin after hypophysectomy and during @a+Ala81 angiotensin II. Infusion of [Sari-Ala”] angiotensin
II (10 pg/min iv) after hypophysectomy caused an increase in superior mesenteric arterial conductance that reached a new plateau about 10 min after beginning the infusion (Fig. 3). The values recorded 10 min after beginning the infusion were significantly different from the control values recorded immediately before the infusion began (P < 0.01). Associated with the vasodilatation was a fall in arterial pressure from 123 t 2 to 110 t 2 mmHg (P c 0.01). Thus, in the absence of the pituitary gland, circulatory angiotensin II appears to exert a large vasoconstrictor influence on the mesenteric resistance vessels in the anesthetized, laparotomized cat. In the absence of the pituitary gland and a functioning renin-angiotensin system, each dose of vasopressin caused a significantly larger (P < 0.05) decrease in mesenteric conductance as a percentage of control than had occurred in intact animals (Fig. 1). Again, comparison of absolute conductance values indicates that the most dramatic effect of the angiotensin II antagonist in hypophysectomized animals occurred in the lower dosage range (Fig. 2). Thus 0.5 mU/(min. kg) of vasopressin caused mesenteric conductance to decrease from 0.281 to 0.201 ml/(mine kg*mmHg), a 6.7-fold greater decrease than had occurred in intact animals (P c 0.01) and a 1.7-fold greater decrease than had occurred after hypophysectomy (P < 0.01). As the dosage of vasopressin increased, the conductance values recorded in response to a particular dose of the drug approached the corresponding values recorded earlier; thus the decrement in conductance was similar to what had occurred during the first two infusions. Therefore, in the higher dosage range, the pituitary gland and renin-angiotensin system appear to exert little influence on the responsiveness of the mesenteric resistance vessels to vasopressin, and the influence of these factors was evident only in the lower dosage range. The values for femoral arterial pressure recorded during 2.0, 5.0, and 10.0 mU/(min.kg) of vasopressin
were significantly different (P c 0.0025) from the preinfusion control value (Fig. 2). These doses of vasopressin caused a small, but significantly larger (P < 0.05), increase in arterial pressure (percent control, Fig. 1) than had occurred in intact animals, although the increase was not significantly different (P > 0.5) from that which occurred after hypophysectomy alone (Fig. 1) ‘Repeated dose-response curves in intact
animals.
Three dose-response curves to vasopressin were obtained in each of two cats. The second and third doseresponse curves in each cat were very similar to the first curve obtained in the same cat. It appeared that the sensitivity of the mesenteric resistance vessels to vasopressin does not change significantly with time or with previous exposure to vasopressin, and that the changes in sensitivity observed in other experiments were due to the interventions of hypophysectomy and the angiotensin II antagonist. DISCUSSION
The observation that hypophysectomy and [SariAla81 angiotensin II caused an increase in mesenteric conductance suggests that circulating vasopressin and angiotensin exert a major vasoconstrictir influence on the mesenteric resistance vessels in the anesthetized surgically stressed cat. It has not been proven that the effects of hypophysectomy were due solely to removal of the vasopressin system. However, following removal of the gland, conductance increased slowly and, in all animals, reached a new plateau 15-30 min later. The time course of this vasodilatation was similar to that of stopping a vasopressin infusion and parallels the predicted rate of elimination for vasopressin. Assuming the half-life of vasopressin in the anesthetized animal is approximately 5-6 min (10) and that it requires 4 to 5 half-lives for a compound eliminated by first-order kinetics to reach new steady-state levels, it follows that circulating levels of vasopressin should approach negligible values 20-30 min after removal of the major source
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H204
PANG,
of the hormone. On the basis of these observations and assumptions, we interpret the changes in conductance that follow hypophysectomy as primarily due to elimination of circulating vasopressin. The effects of [SariAlas] angiotensin II are more easily interpreted. The compound is a weak partial agonist (17). It competitively antagonizes angiotensin II and has little other known biological activity (20). The vasodilatation caused by hypophysectomy and [Sari-Ala81 angiotensin II are in agreement with other data from our laboratory (14) and we conclude that the high arterial pressure and low mesenteric conductance observed in acute experiments is in part due to the vasoconstrictor action of circulating vasopressin and angiotensin. We also conclude that the effect of these endogenous peptides on the mesenteric resistance vessels reduces the apparent sensitivity of these vessels to exogenous vasopressin. Except for the largest dose of 10 mU/ (min kg) of vasopressin, the responses recorded in our intact animals (Fig. 1) closely .matched those reported by Cohen et al. Our combined results indicate that the mesenteric resistance vessels in the cat appear relatively unresponsive to 0.5 mU/(min kg) of vasopressin. In the dog, 2 and 4 mU/(min kg) of vasopressin caused no significant change in mesenteric conductance and 8 mU/(min kg) was required to induce a significant change in this parameter (23). However, this apparent lack of sensitivity appears to be in part due to the influence of the vasopressin system and renin-angiotensin system since 0.5 mU/(min kg) of vasopressin, a dose which caused only a small change in conductance in intact animals, caused a 6.7-fold greater change in conductance when the influence of these systems were absent (Fig. 2). The lack of effect of 0.5 mU/(min . kg) of vasopressin in intact animals may be due to several factors. It can be argued that the ineffectiveness of this dose of vasopressin is because the mesenteric bed is already constricted and that we are approaching the plateau level of the dose-response curve. This may well be part of the explanation. However, since baroreceptor activity influences vasopressin secretion (26) and since vasopressin appears to account in part for the constricted state of the mesenteric bed in our intact animals, it seems reasonable to assume that administration of a vasoconstrictor agent would cause reflex inhibition of vasopressin secretion and that concurrent inactivation of circulating vasopressin should then’ constitute a vasodilator influence which opposes the vasoconstrictor activity of exogenous vasopressin. Consistent with this assumption is the observation that infusion of the pressor agent, norepinephrine, suppresses the release of vasopressin (1, 27) via the baroreceptor reflex (1). It seems likely that infusion of a&other vasoconstrictor agent, vasopressin, also should cause reflex inhibition of vasopressin secretion. Thus the small effect of 0.5 mU/ (min. kg) of vasopressin in animals with a functioning vasopressin system may be due in part .to two opposing influences: the vasoconstrictor action of exogenous vasopressin and the withdrawal of the vasoconstrictor influence of endogenous vasopressin. Because intravenous infusions of vasopressin inhibit renin release (3, l
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WILCOX,
AND
McNEILL
24, 30, 31), it is tempting to suggest that withdrawal of the vasoconstrictor influence of the renin-angiotensin system may also have contributed to the lack of potency of vasopressin in intact animals. However, the half-life of renin is long (6) and although the secretion rate of renin may be reduced in our experiments during in% sion of vasopressin, plasma renin activity and the circulating levels of angiotensin may fall only slowly. In view of these considerations, we suggest that the ineffectiveness of low doses of vasopressin on the mesenteric resistance vessels in the anesthetized, surgically stressed animal is due in part to the already constricted state of the bed caused by endogenous vasopressin and angiotensin, and in part due to an opposing vasodilator influence, namely the reflex inhibition of vasopressin secretion and concurrent elimination of endogenous vasopressin. Despite marked vasoconstriction of the mesenteric resistance vessels by vasopressin, the increases in femoral arterial pressure were small. Since other vascular beds respond to vasopressin, and total peripheral resistance is elevated (23), it is likely that cardiac output was reduced during our infusions, a probability consistent with the role of total peripheral resistance in the control of venous return (9), and an observation reported to occur in the dog ,during infusions of vasopressin (23). The small changes in arterial pressure are consistent also with an active baroreceptor reflex. Cowley, Monos, and Guyton showed that doses of vasopressin which caused marked pressor responses in baroreceptor-denervated conscious dogs caused little change in blood pressure when the buffer action of the baroreceptor reflex was intact and allowed to compensate (5), a finding which confirmed an earlier report in the anesthetized dog (22). In our experiments, reflex withdrawal of sympathetic nervous system activity also may have attenuated the pressor response to exogenous vasopressin at least partly by reducing the tone in capacitance vessels, thereby contributing to the fall in venous return and cardiac output. The change in mesenteric conductance caused by doses as low as 0.5 mU/(min . kg) of vasopressin suggests a role for this hormone in the control of mesenteric conductance under certain pathophysiological conditions. Although data on the plasma clearance of vasopressin in the cat is inadequate, the mean plasma clearance values for vasopressin in the pentobarbitalanesthetized dog ranged from 10.0 to 14.9 ml/(min kg) in six different studies (10). Since the half-life of the hormone in the cat is similar to that in the dog (10) and assuming the volume of distribution is similar in the two species, then the plasma clearance of vasopressin in the cat may also be similar to that found in the dog. Thus an infusion of 0.5 mU/(min 9kg) of the drug should cause an elevation in the steady-state plasma concentration of vasopressin in the range of 34 to 50 @/ml in our hypophysectomized animals, a level within the range reported to occur following major surgery (2, 19) or mild blood loss (lo-15% of blood volume) (25, 26, 28). These findings on the sensitivity of the mesenteric resistance vessels to vasopressin are consistent with other data suggesting an important role for vasopressin
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VASOPRESSIN
ON INTESTINAL
RESISTANCE
H205
VESSELS
in the control of the mesenteric resistance vessels following major surgery (14), and in the mechanism of the intestinal vasoconstriction following volume depletion induced by hemorrhage (l5), or by administration of diuretics (13, 16).
We are indebted to the Saskatchewan Heart Foundation and to Our Lady of the Prairies Foundation for grants in support of this work. We thank Dr. A. W. Castellion of the Norwich Pharmacal. c o. f or a generous supply of [Sari-Ala81 angiotensin II. C. C. Y. Pang is a fellow of the Canadian Heart Foundation. Received 20 June 1977; accepted in final form 28 August 1978.
REFERENCES 1. BERL, T., P. CADNAPAPHORNCHAI, J. A. HARBOTTLE, AND R. W. SCHRIER. Mechanism of suppression of vasopressin during alphaadrenergic stimulation with norepinephrine. J. CZin. Invest. 53: 219-227,1974. 2. BONJOUR, J. P., AND R. L. MALVIN. Plasma concentrations of ADH in conscious and anesthetized dogs. Am. J. Physiol. 218: 1128-1132,197O. 3. BUNAG, R. D., I. H. PAGE, AND J. W. MCCUBBIN. Inhibition of renin release by vasopressin and angiotensin. Cardiovas. Res. 1: 67-73,1967. 4. COHEN, M. M., D. S. SITAR, J. R. MCNEILL, AND C. V. GREENWAY. Vasopressin and angiotensin on resistance vessels of spleen, intestine, and liver. Am. J. Physiol. 218: 1704-1706, 1970. 5. COWLEY, JR., A. W., E. MONOS, AND A. C. GUYTON. Interaction of vasopressin and the baroreceptor reflex system in the regulation of arterial blood pressure in the dog. Circ. Res. 34: 505-514, 1974. 6. LARAGH, J. H., AND J. E. SEALEY. The renin-angiotensin-aldosterone hormonal system and regulation of sodium, potassium, and blood pressure homeostasis. In: Handbook of Physiology. RenaZ Physiology, edited by J. Orloff and R. W. Berliner. Washington, D.C.: Am. Physiol. Sot., 1973, sect. 8, p. 831-908. 7. JOHNSON, M. D., AND R. L. MALVIN. Plasma renin activity during pentobarbital anesthesia and graded hemorrhage in dogs. Am. J. Physiol. 229: 1098-1101,1975. 8. JOHNSON, P. C. Autoregulation of intestinal blood flow. Am. J. PhysioZ. 199: 311-318, 1960. 9. JONES, C. E.; E. E. SMITH, AND J. W. CROWELL. Cardiac output and physiological mechanisms in circulatory shock. In: i&?P InternationaL Review of Science. Cardiovascular PhysioZogy, edited by A. C. Guyton and C. E. Jones. Baltimore: University Park Press, 1974, ser. 1, vol. 1, p. 233-258. 10. LAUSON, H. D. Metabolism of the neurohypophysial hormones. In: Handbook of PhysioZogy: Endocrinology, edited by R. 0. Greep and E. B. Astwood. Washington, D.C.: Am. Physiol. Sot. 1974, sect. 7, vol. 4, p. 287-393. 11. MCKENZIE, J. K., J. W. RYAN, AND M. R. LEE. Effect of laparotcmy on plasma renin activity in the rabbit. Nature 215: 542-543,1967. 12. MCNEILL, J. R. Escape of intestinal resistance vessels to angiotensin II. Can. J. Physiol. PhurmacoZ. 52: 458-464,1974. 13. MCNEILL, J. R. Intestinal vasoconstriction following diureticinduced volume depletion: role of angiotensin and vasopressin. Can. J. Physiol. PharmacoZ. 52: 829-839, 1974. 14. MCNEILL, J. R., W. C. WILCOX, AND C. C. Y. PANG. Vasopressin and angiotensin: reciprocal mechanisms controlling mesenteric conductance. Am. J. Physiol. 232: H260-H266, 1977 or Am. J. PhysioZ.: Heart Circ. Physiol. 1: H260-H266,1977. 15. MCNEILL, J. R., R. D. STARK, AND C. V. GREENWAY. Intestinal vasoconstriction after hemorrhage: roles of vasopressin and angiotensin. Am. J. Physiol. 219: 1342-1347, 1970. 16. MCNEILL, J. R., W. C. WILCOX, AND R. REGNAULT. Effect of SariAla8 angiotensin II and hypophysectomy on the intestinal resistance vessels and blood pressure following furosemide-induced volume depletion. Can. J. PhysioZ. Pharmacol. 54: 373-380,1976.
17. MIMRAN, A., K. J. HINRICHS, AND N. K. HOLLENBERG. Characterization of smooth muscle receptors for angiotensin: studies with an antagonist. Am. J. Physiol. 226: 185-190, 1974. 18. MONOS, E., E. KOLTAY, AND A. G. B. KOVACH. Adrenal blood flow and corticosteroid secretion: III. Effect of vasopressin on blood circulation and corticosteroid secretion in the dog before and after acute hypophysectomy. Actu Physiol. Acad. Sci. Hung. 31: 149-157,1967. 19. MORAN, H., F. W. MILTENBERGER, W. A. SHUAYB, AND B. ZIMMERMANN . The relationship of antidiuretic hormone secretion to surgical stress. Surgery 56: 99-108,1964. 20. PALS, D. T., F. D. MASUCCI, G. S. DENNING JR., F. SIPOS, AND D. C. FESSLER. Role of the pressor action of angiotensin II in experimental hypertension. Circ. Res. 29: 673-681, 1971. 21. PETTINGER, W. A., K. TANAKA, K. KEETON, W. B. CAMPBELL, AND S. N. BRINKS. Renin release, an artifact of anesthesia and its implications in rats. Proc. Sot. Exp. BioZ. Med. 148: 625-630, 1975. 22. ROCHA E SILVA M., JR., AND M. ROSENBERG. The release of vasopressin in response to hemorrhage and its role in the mechanism of blood pressure regulation. J. PhysioZ. London 202: 535-557,1969. 23. SCHMID, P. G., F. M. ABBOUD, M. G. WENDLING, E. S. RAMBERG, A. L. MARK, D. D. HEISTAD, AND J. ‘W. ECKSTEIN. Regional vascular effects of vasopressin: plasma levels and circulatory responses. Am. J. Physiol. 227: 998-1004,1974. 24. SHADE, R. E., J. 0. DAVIS, J. A. JOHNSON, R. W. GOTSHALL, AND W. S. SPIELMAN. Mechanism of action of angiotensin II and antidiuretic hormone on renin secretion. Am. J. PhysioZ. 224: 926-929,1973. 25. SHADE, R. E., AND L. SHARE. Vasopressin release during nonhypotensive hemorrhage and angiotensin II infusion. Am. J. PhysioZ. 228: 149-154,1975. 26. SHARE, L. Blood pressure, blood volume and the release of vasopressin. In: Handbook of Physiology. Endocrinology, edit.ed by R. 0. Greep and E. B. Astwood. Washington, D.C.: Am. Physiol. Sot., 1974, sect. 7, vol. 4, p. 243-256. 27. SHIMAMOTO, K., AND M. MIYAHARA. Effect of norepinephrine infusion on plasma vasopressin levels in normal human subjects. J. CZin. EndocrinoZ. Metab. 43: 201-204, 1976. 28. SZCZEPANSKA~ADOWSKA, E. The activity of the hypothalamohypophysial antidiuretic system in conscious dogs I. The influence of isosmotic blood volume changes. Pfluegers Arch. 335: 139-146, 1972. 29. SZCZEPANSKA-SADOWSKA, E. Hemodynamic effects of a moderate increase of the plasma vasopressin level in conscious dogs. Pfluegers Arch. 338: 313-322,1973. 30. TAGAWA, H., A. J. VANDER, J-P. BONJOUR, AND R. L. MALVIN. Inhibition of renin secretion by vasopressin in unanesthetized sodium-deprived dogs. Am. J. PhysioZ. 220: 949-951,197l. 31. VANDER, A. J. Inhibition of renin release in the dog by vasopressin and vasotocin. Circ. Res. 23: 605-609, 1968. 32. WAGNER, JR.,’ H. N., AND E. BRAUNWALD. The pressor effect of the antidiuretic principle of the posterior pituitary in orthostatic hypotension. J. CZin. Invest. 35: 1412-1418, 1956.
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